Mucous membrane pemphigoid is an autoimmune
or "self-allergy" disease in which a patientís own
circulating antibodies become altered so that they attack the fibrous
attachment of the skin and membrane epithelium to the underlying
connective tissues. Women are more commonly affected than men and the
disease is usually diagnosed between the ages of 40-60 years. The
typical lesion is a small or large, clear-fluid blister which breaks
fairly rapidly in the mouth to leave a flat white, somewhat tender
ulcer with a thin red line around it. The gums are especially likely
to be involved, resulting in sloughing during eating or tooth brushing
("desquamative gingivitis"). Usually patients with oral
involvement will lack major skin involvement, but the eyelids and
genital mucosa are quite susceptible to the blistering phenomenon.
There is no cure for this pemphigus vulgaris look-alike disease, but
lesions frequently respond well to topical or systemic
corticosteroids. Death from this disease is extremely rare, but scar
formation of the eyelids and eyeball surfaces may lead to blindness if
the eyes are not closely monitored by an ophthalmologist.

Mucous membrane pemphigoid, also
known as benign mucous membrane pemphigoid and cicatricial
(scar-forming) pemphigoid, is one of a number of
blister-producing autoimmune mucocutaneous diseases under the pemphigoid
designation. It is the variant most likely to occur in the mouth and other
membranes of the body. While similar in its clinical presentation to pemphigus
vulgaris, is is much less severe and the involved antibodies attack the
attachment fibrils (Type VII collagen) of the basement membrane rather than the
desmosomal attachments between epithelial cells, as occurs in pemphigus.
The antibodies react specifically against at least two hemidesmosome antigens,
BPAG1 and BPAG2, collectively called the "bullous pemphigoid antigen,"
which bind the basal cell layer of the epithelium to the basement membrane. This
results in separation of the epithelium from the underlying stroma at the level
of the lamina lucida, the electron lucent zone found between the basal cell
membrane and lamina densa.

The effect may be quite localized, as circulating
autoantibodies are not present in a large proportion of affected individuals, or
are present only at low titers using indirect immunofluorescence techniques. The
membranes of the mouth, eyes, larynx, pharynx and genital region may all be
affected, but conjunctival mucosal involvement is likely the most severe problem
because of the propensity for scar formation and eventual blindness.
Compared to pemphigus vulgaris, the disease runs a rather benign, protracted
course, with at least a third of patients eventually developing skin involvement
of the head and neck region, legs or genitalia. Additionally, half of all
patients will develop bullae of other membranes of the upper aerodigestive
tract, the anus or genitalia. There is an increased frequency of certain HLA
tissue types, especially HLA-B12, HLA-DR4 and Dqw7, and some drug-induced cases
have also been associated with different HLA types.

This disease is characterized by bullous lesions of mucous membranes, especially
oral and conjunctival membranes. Eye involvement results in scar formation or
fibrous synechiae of palpebral and bulbar conjunctivae, with entropion and
blindness occurring in almost a third of untreated cases (Figure
1). Disease onset is usually between 40 and 60 years of patient age, and
oral lesions are the first manifestation of disease in two-thirds of cases.
There is no racial or ethnic predilection, but the disease is much more common
in women than in men (male:female ratio = 1:2).

Individual lesions develop slowly and are usually smaller and less frequent
during the early months or years of the disease (Figures
2 & 3). Bullae may, however, become more than 3 cm. in diameter (Figure
4) and may remain intact long enough for the clinician to see them as clear
or slightly bluish blisters. While there is seldom a surrounding inflammatory
halo, the mucosa in the affected region may be quite diffusely erythematous and
at least 10% of patients will have a positive Nikolsky test (creation of a
blister by pressure or friction). A ruptured blister leaves a
shallow, mildly tender ulcer bed which heals in 7-10 days. Large or secondarily
infected lesions may result in scar formation, but this phenomenon is much less
severe than it is with conjunctival involvement.

Oral sites most often involved include the gingiva (90% of oral cases),
palate and buccal mucosa. While individual blisters do not necessarily recur at
the same exact site, new lesions do seem to remain contained within a limited
anatomic region. When only the gingiva or alveolar mucosa are involved, the
disease has a special tendency to remain localized, and this has led some
authorities to prefer the more generic term, desquamative
gingivitis. Desquamative gingivitis is, however, a term also used to
describe gingival manifestations of pemphigus and bullous
lichen planus.

Oral bullae demonstrate separation of the
epithelium from the basement membrane (Figure 5),
often with small numbers of chronic and acute inflammatory cells, including
eosinophils, in the extracellular serous fluid of the blister. Only rarely will
chronic inflammatory cells be seen within the subepithelial stroma of a fresh,
unruptured lesion. Most lesions, however, are ruptured at the time of biopsy,
hence, the subepithelial separation may only be found at the edge of an
otherwise nonspecific inflammatory ulceration. Direct immunofluorescence will
demonstrate in almost all cases a continuous linear band of IgG and C3
immunoreactants along the basement membrane (Figure 6).
More than half of all patients will also have circulating autoantibodies
identifiable in the serum through indirect immunofluorescence.

Pemphigoid is distinguished from pemphigus by the vertical location of the
blister: the latter produces acantholysis with cleavage of the spinous cell
layer, while the former produces cleavage of the basement membrane region. Other
entities can create subepithelial cleavage or blistering, including linear
IgA disease, bullous lichen planus, epidermolysis
bullosa (hereditary and acquired forms), bullosa
hemorrhagica, erythema multiforme, bullous
pemphigoid and dermatitis herpetiformis.

The ruptured blisters of adult onset linear IgA are very similar except that
there is typically a neutrophilic infiltrate along the basement membrane and
surrounding the blood vessels of the subepithelial stroma.Neutrophilic microabscesses may be present within the connective tissue papillae
and on direct immunofluorescence linear deposits of IgA are seen along the
basement membrane. Eruptions identical in every way to linear IgA have occurred
with the use of lithium, vancomycin, diclofenac, and glibenclamide.

Dermatitis herpetiformis has an histopathologic
appearance similar to linear IgA disease, except that the basement membrane
deposits of IgA have a more irregular or granular appearance. It also presents
typically with small, viral-like vesicles rather than the larger bullae of
pemphigoid or linear IgA.

Bullous lichen planus has a distinct band of
chronic inflammatory /immunological cells immediately beneath the epithelium,
which usually makes it easy to distinguish it from pemphigoid. A loss of rete
ridges or the formation of saw-toothed ridges are also characteristically found,
as is liquefactive (hydropic, ballooning) degeneration of the basal cells and a
thickened surface layer of parakeratin. There are, however, occasional cases
with lichenoid light microscopic changes and characteristic pemphigoid
immunofluorescence.

Routine histopathology will often not distinguish between epidermolysis
bullosa acquisita(EBA) and pemphigoid, and
at least half of EBA patients have involvement of the oral mucosa.
Immunofluorescence will, however, show IgG isoantibody deposition on the floor
of the EBA bulla, while antibodies coat the roof of the blister in pemphigoid.
In EBA, the blisters arise beneath the basal lamina, where the anchoring fibrils
(Type VII collagen) are destroyed. EBA may, moreover, be associated with Crohnís
disease and other inflammatory bowel diseases,
rheumatoid arthritis, systemic
lupus erythematosus, idiopathic pulmonary fibrosis,
and chronic thyroiditis. Hereditary epidermolysis
bullosa is more easily distinguished by its childhood onset and its classic
acral distribution.

Erythema multiforme bullosa can present with
subepithelial or intraepithelial cleavage, or both together, but it typically
also has subepithelial edema and infiltration by mixed inflammatory cells,
including eosinophils. Subepithelial vesiculation is seen in association with
necrotic basal keratinocytes, while pemphigoid basal cells remain intact. Many
cases cannot, however, be distinguished from pemphigoid using histopathologic
and immunoreactive features, and the diagnosis is often based on the clinical
presentation and exclusion of other vesiculobullous disorders. Erythema
multiforme not only occurs at a younger age than pemphigoid, but it typically
has a duration of limited to weeks or months while pemphigoid remains an
incurable disease.

Oral pemphigoid can often be controlled by topical or systemic
corticosteroids or other immunosuppressive agents, particularly
cyclophosphamide, but there is no cure for this disease. Lesions occur
intermittently and may affect different parts of the oral mucosa at different
times. Seldom do blisters occur elsewhere in the upper aerodigestive tract, but
patients with laryngeal or esophageal involvement will develop dysphagia or
esophageal webs. Ocular involvement eventually becomes manifested in 50-85% of
cases and skin involvement is eventually seen in up to 30% of cases. The patient
should be followed carefully by an ophthalmologist whether or not conjunctival
involvement is seen at the time of oral lesion diagnosis.